This invention is in the fields of biochemistry, pharmacology, and anti-viral agents.
There is a major need for methods to prevent the spread of viruses that are transmitted through sexual contact, including genital herpes viruses (herpes simplex virus type 2, HSV-2), the human immunodeficiency virus (HIV, the causative agent of AIDS), hepatitis viruses, and papilloma viruses. Extensive information on each of these viruses is contained in numerous medical books and articles; for example, Mindel 1989 offers a good overview of herpes viruses, while the October 1988 issue of Scientific American offers a good overview of HIV and AIDS.
Once contracted, herpes and HIV are incurable, since the viruses insert their DNA into the chromosomes of infected cells. The fact that these viruses are incurable highlights the need for methods to reduce the rates and incidence of infection among people who are not yet infected. The subject invention is directed solely toward that goal. This invention is not a treatment for people who are already infected with herpes, HIV, or any other sexually transmitted virus; instead, it is a method of reducing the risk of infection among people who are not infected, but who may be exposed to sexually transmissible viruses through intercourse with potentially infected sexual partners. Briefly, this invention involves topical lubricants that are spread on the surfaces of the genitals before and during sexual intercourse, which contain a selected zinc salt as an anti-viral agent. The lubricant must be non-irritating, physiologically acceptable, and free of any adverse long-term effects when used frequently over a prolonged period of time. Preferred zinc salts include relatively low molecular weight organic salts which have high solubility in water, and which have low pK values (which indicates high levels of ionic dissociation to release free divalent zinc ions, Zn.sup.++). Such salts include zinc acetate and zinc propionate. Other organic salts that have somewhat lower levels of solubility or dissociation, but which can be used if desired, include zinc butyrate, formate, gluconate, glycerate, glycolate, and lactate. All of these organic salts which have been tested to date have not caused any irritation in skin, genital, or intercourse tests. By contrast, zinc sulfate (which has been used in the past by numerous other researchers trying to find effective ways to treat herpes infections) causes significant levels of irritation in most people, and is not preferred. Although substantial irritation will be tolerated by people who are already infected by genital herpes and who are suffering an outbreak of lesions, such levels of irritation are not acceptable in a genital lubricant intended for use during sexual intercourse.
Prior Studies on Zinc Salts To Treat Genital Herpes
Prior to this invention, numerous researchers reported that zinc could inhibit herpes viruses. Some of these test reports involved in vitro cell culture tests (e.g., Gordon et al 1975, Shlomai et al 1975, Gupta and Rapp 1976, Fridlender et al 1978, and U.S. Pat. No. 4,407,818 by Lionelle et al). Other test reports involved people or lab animals that had already become infected with herpes viruses (e.g., DeRoeth et al 1963, Jones 1979, Tennican et al 1979 and 1980, Fahim et al 1980a and 1980b, Wahba et al 1980, Brody et al 1981, Eby and Halcomb 1985, and U.S. Pat. Nos. 4,465,666 and 4,762,715 (Lukas et al)).
Most of that work was done before the advent of nucleoside analogs such as acyclovir and gancyclovir. Interest in zinc as a topical anti-herpetic treatment dropped off sharply after the "high-tech" drugs such as acyclovir offered more effective treatments.
It should also be noted that several of the articles cited above report that zinc salts, by themselves, are not effective in inhibiting herpes viruses unless they are combined with some other agent or treatment that increases the effectiveness of the mixture. For example, the reports by Fahim et al involve ultrasound treatment of areas treated by ointments containing 30% urea, 3% zinc sulfate, and 2% tannic acid. Obviously, ultrasound treatment of the site of transmission during sexual intercourse is not feasible.
Similarly, U.S. Pat. No. 4,465,666 (Lukas et al) stated that zinc salts by themselves were not adequately active against herpes viruses. In order to render the zinc salts effective for treating herpes, Lukas '666 stated that a sulfated polysaccharide such as heparin or dextran sulfate had to be added to the mixture. However, it would be inadvisable to add heparin or dextran sulfate to a genital lubricant, since repeated use of either agent in a genital lubricant could generate severe adverse effects. Heparin is a powerful anti-coagulant, and it inhibits the growth of epithelial cells, which are the type of cells that line the mucous membranes inside the vagina and urethra (Wright et al 1985 and 1987). Both of these traits indicate that heparin is likely to interfere with the closure and healing of any lesions, cuts, and microabrasions in the mucous membranes or other genital surfaces. Heparin administration has also been associated with skin necrosis (White et al 1979), and heparin apparently is able to penetrate the skin and enter the bloodstream (Aliabeva et al 1980). All of these factors indicate that heparin would generate various risks of adverse effects in substantial portion of the general population.
Dextran sulfate appears to be even more dangerous. It causes severe ulcerations and inflammation in the colon which can lead to colon cancer; this effect is so strong that dextran sulfate is used as the causative agent in a standard laboratory technique which induces ulcerative colitis and colon cancer in lab animals (e.g., Cooper et al 1993 and Yamada et al 1992). It also interferes with fibroblast growth, various types of fluid and cell movement and permeation, and other natural processes involving the skin (see Sorimachi et al 1992, Van Osselaer et al 1993, and Powis et al 1992). In addition, dextran sulfate is also an anti-coagulant. Although less powerful than heparin, it can also interfere with the healing and closure of lesions or small cuts or abrasions in the skin or mucous membranes of the genitals.
These adverse effects are regrettable, since both heparin and dextran sulfate have been shown to have substantial activity in cell culture tests against HIV, the virus that causes AIDS. However, these risks and adverse effects cannot be ignored, and they apparently render heparin and dextran sulfate dangerous and unsuitable for use in genital lubricants. It should be noted that U.S. Pat. No. 4,869,270 (Ueno et al 1989), which claimed the use of dextran sulfate in a condom lubricant, made no mention of the problem of ulcerative colitis caused by dextran sulfate, or any of the other physiological problems and dangers listed above.
It should also be noted that most of the above-cited reports involving herpes viruses used zinc sulfate, which causes genital irritation and is therefore not well suited to use as a lubricant during intercourse.
Studies on Zinc Which Failed to Show Inhibition of HIV
A number of researchers have performed screening studies on various zinc compounds, to determine whether such compounds might be able to inhibit HIV, the virus that causes AIDS. However, none of the published studies that used standardized assays showed any effectiveness for zinc as an anti-HIV agent. Very little has been published in scientific or medical journals regarding such tests, since the results were poor; however, the lack of success using zinc against HIV can be documented using items of personal correspondence.
For example, when the Applicant submitted samples of several zinc salts (including zinc acetate and zinc gluconate) to the National Cancer Institute for evaluation in a standardized screening test used to evaluate drugs against HIV (described in Weislow et al 1989), the scientists in charge of the NCI's screening program returned the zinc salts without even opening them. The NCI's letter of response addressed to the Applicant, dated Aug. 8, 1991, stated as follows: "After careful consideration, we have decided not to test your zinc salts in our AIDS-antiviral assay . . . We have tested 36 zinc-containing compounds in our in vitro AIDS screen, including zinc gluconate. Test results of this inactive compound, NSC 619899, are enclosed . . . None of these materials has demonstrated any activity worth pursuing . . . Based on these results, we don't believe that your compounds will show activity in our assay."
This is an authoritative statement by researchers skilled in the art of HIV research who had tested zinc against HIV, and who did not believe that zinc salts could serve as effective agents against HIV infection.
The Applicant has also been informed by an official of Contraceptive Research and Development (CONRAD, a not-for-profit foundation based in Alexandria, Va.) that several zinc salts were tested using an assay described in Resnick et al 1990. According to the CONRAD official, the results of those tests did not show any substantial anti-HIV activity for any zinc compounds.
Other Prior Art
Another line of prior art also deserves mention, even though it does not involve anti-viral research. In the late 1970's, several zinc salts were studied to determine whether they might be effective as contraceptives to avoid pregnancy (Williams 1980, Chvapil 1978, and Chvapil 1980). Williams 1980 tested several formulations, including zinc acetate mixed with K-Y Lubricating Jelly (a trademark for an aqueous gel sold by Johnson & Johnson, New Brunswick, N.J.). The zinc salts tested by Williams and Chvapil were only about 80% effective on a single-event basis. This is not nearly good enough for practical and effective use as a contraceptive; to be effective as a contraceptive at a 95% or higher level over the span of a year or more (where a failure in any single act of intercourse, out of numerous acts of intercourse during the year, results in pregnancy), a contraceptive must be effective at well over the 99% level during each act of intercourse. Since the results reported by Williams and Chvapil showed that zinc salts did not have adequate contraceptive activity, interest in this line of research died out, and a gel containing a zinc salt apparently was never packaged and distributed for sale or further testing for contraceptive use.
Accordingly, there remains a need for a non-irritating, non-toxic genital lubricant for use during sexual intercourse, to reduce the risk of viral infection in someone who is not previously infected. Any such lubricant must be safe and harmless enough for frequent and repeated use (such as daily use) over a period of months or years (obviously, terms such as repeated or daily use do not imply that the same quantity of lubricant will be used repeatedly; instead, a new quantity of the lubricant will be used during each act of intercourse). The lubricant gel must also be free of any component which is an anti-coagulant (such as heparin or dextran sulfate) or which could pose a risk of adverse effects due to frequent and repeated use over a span of months or years.
One object of this invention is to disclose an article of manufacture comprising such a lubricant, enclosed within a package that renders the lubricant convenient and easy to use, with or without a condom. Such packaging can help promote consistent use during each and every act of intercourse, to provide maximal effectiveness.